tbuckley/cabot-search huggingface dataset:
LGG-13. The clinical and molecular characteristics of progressive hypothalamic/optic pathway pilocytic astrocytoma
Authors: Xiaoyu Li, Daniel Moreira, Asim Bag, Ibrahim Qaddoumi, Sahaja Acharya, Jason Chiang
Journal: Neuro-Oncology (2022)

Abstract Unresectable hypothalamic/optic pathway pilocytic astrocytoma (PA) can be challenging to manage due to repeated progressions despite multiple lines of therapy. To identify clinical and biologic factors associated with tumor progression, we retrospectively identified 72 unresectable non-NF1-associated hypothalamic/optic pathway PA. Tumors were classified as high-risk (50%) if they progressed after three or more lines of chemotherapy/targeted therapy, progressed after radiation, developed metastatic disease, or died of disease. DNA methylation profiling and transcriptome analysis (RNA sequencing) were performed on treatment-naïve tumors with available tissue (n=40), and the findings were validated by immunohistochemistry (IHC) on additional tumor tissue. The median follow-up of the entire cohort was 12.3 years. High-risk tumors were associated with male sex (M:F = 2.6:1), younger age at diagnosis (median 3.2 years vs. 6.7 years, P = 0.005), and high incidence of KIAA1549-BRAF fusion (81.5% vs. 38.5%, P = 0.0032). High-risk tumors demonstrated decreased CpG methylation and increased RNA expression in many mitochondrial genes and genes downstream of E2F and NKX2.3 transcription factors. Transcriptome analysis identified transcription factor TBX3 and proto-oncogene serine/threonine protein kinase PIM1 as common downstream targets of both E2F and NKX2.3 and potential drivers of tumor progression. IHC confirmed increased expression of TBX3 and PIM1 in high-risk tumors. PIM1 is known to increase the stability and transcriptional activity of MYC, and gene enrichment analysis identified enrichment of MYC targets. Signaling pathways known to be implicated in PA, such as MAPK and PI3K/AKT/mTOR, were also enriched, in addition to pathways related to mitochondrial biogenesis and oxidative phosphorylation. Our results support the model in which the p53-PIM1-MYC axis and TBX3 act alongside MAPK and PI3K/AKT/mTOR pathways to promote tumor progression, highlighting potential new targets for combination therapy and refining disease prognosis.
TBIO-12. Screening for Cancer Predisposition Syndromes in Pediatric Neuro-Oncology Patients: a Single Institution Experience
Authors: Claire Johns, Cassie Kline, David Solomon, Sabine Mueller, Anu Banerjee, Nalin Gupta, Alyssa Reddy
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND: Traditional screening for cancer predisposition syndromes centers on family history, phenotypic features, and tumor histology. With expanded accessibility of next generation sequencing, identification of de novo germline mutations is increasing and the predictive value of family history has become less clear. While identification of germline mutations often affects care of pediatric neuro-oncology patients, germline sequencing is not currently standard of care. We hypothesize that routine screening for germline mutations in pediatric neuro-oncology patients reveals unsuspected cancer predisposition syndromes and impacts care. METHODS: A retrospective analysis was performed on pediatric neuro-oncology patients at a single institution who had targeted next generation sequencing of approximately 500-cancer associated genes (UCSF500) on tumor and paired germline DNA. We determined the proportion of patients with germline mutations and assessed impact on future screening and current tumor treatment. We interrogated clinical notes, family history, and interviewed treating physicians to determine if predispositions were previously suspected. RESULTS: Between June 2015-December 2019, 187 patients had paired testing; of these 29 (16%) harbored germlines mutations that were pathogenic or likely pathogenic. Germline mutations were found in patients with high-grade glioma (n=12), low-grade glioma (n=7), medulloblastoma (n=4), ATRT (n=2), and choroid plexus papilloma (n=1). Known cancer predisposition syndromes were identified or confirmed in 18 patients. Of these, the most common alterations were in TP53 (n=6), CHEK2 (2), NF1 (n=2), SMARCB1 (n=2), and PTEN (n=2). Patients were referred to genetic counseling in 26 cases and malignancy screenings were implemented in 25 cases. Germline findings affected malignancy treatment in 10 cases, most often through use of targeted therapeutics or avoidance of radiation. CONCLUSIONS: In our series, we found that 16% of pediatric neuro-oncology patients harbored germline mutations, the majority of which were associated with cancer predisposition syndromes. These results support standardizing screening for pathogenic germline mutations in pediatric neuro-oncology patients.
ATRT-14. Malignant rhabdoid tumors of cranial nerves – ATRT or extracranial rhabdoid tumor?
Authors: Miriam Gruhle, Karolina Nemes, Mona Steinbügl, Pascal D Johann, Irene von Luettichau, Marc Steinborn, Stephan Tippelt, Gudrun Fleischhack, Thomas Lehrnbecher, Susanne Bens, Reiner Siebert, Martin Hasselblatt, Christian Vokuhl, Brigitte Bison, Thomas Kröncke, Patrick Melchior, Beate Timmermann, Michael C Frühwald
Journal: Neuro-Oncology (2022)

Abstract INTRODUCTION: Malignant rhabdoid tumors (MRT) are highly aggressive neoplasias mostly affecting young children. They are classified as rhabdoid tumors of the central nervous system (ATRT, atypical teratoid rhabdoid tumor), rhabdoid tumors of the kidney (RTK) or extracranial rhabdoid tumors arising from any soft tissue outside the central nervous system (eMRT, extracranial extrarenal MRT). We report a series of four MRTs with cranial nerve involvement. METHODS: Patients were identified from a cohort of 132 patients with MRT (2017 – 2021), as part of the European Rhabdoid Registry (EU-RHAB). Diagnosis of MRT was confirmed immunohistochemically with loss of INI1 expression. Details regarding symptoms at first presentation, diagnostic staging, genetic findings, therapy and the course of disease are reported. REPORT OF CASES/RESULTS: The series contains two MRT affecting the trigeminal nerve and two cases with third cranial nerve involvement. They were two female and two male patients with a median age of 4.7 years (1-159 months) at diagnosis. Location of the main tumor mass differed between being located intra- and extracerebrally. Metastases at diagnosis occurred in one patient, a germ-line mutation in SMARCB1 was present in two patients. Two patients received therapy according to EU-RHAB recommendations with an incomplete resection, conventional chemotherapy enhanced by intraventricular methotrexate and radiotherapy. Both patients are currently alive with no signs of progression, one of them bearing a germ-line mutation. Two patients received palliative treatment after surgery due to rapid progression. Median overall survival was 17.3 (1.4-53.1) months. CONCLUSION: MRT of the cranial nerves affect the peripheral nervous system in close proximity to the brain, thus forming a unique sub-entity between ATRT and eMRT. The selected cases provide insight into the particular challenge regarding clear classification, diagnostics and therapy.
Impact of trilaciclib on multilineage chemotherapy-induced myelosuppression events in patients with extensive-stage small cell lung cancer: Post-hoc analyses of data from randomized clinical trials.
Authors: Jerome H. Goldschmidt, Jared Weiss, Jenny Zhou, Jessie Wang, Joshua A. Young, Esteban Lemus Wirtz, Julio Ruiz, Huan Huang, Lowell L. Hart
Journal: Journal of Clinical Oncology (2022)

8568 Background: Trilaciclib is a short-acting CDK4/6 inhibitor administered prior to chemotherapy for multilineage myeloprotection. Reduced occurrence of chemotherapy-induced myelosuppression (CIM) events across neutrophil, red blood cell, and platelet lineages was reported in 3 Phase 2 clinical trials of trilaciclib versus placebo in patients with extensive-stage small cell lung cancer (ES-SCLC). In this post-hoc trial analysis, we further assessed the impact of trilaciclib on the occurrence of single and concurrent multilineage CIM events. Methods: Analyses were conducted separately by line of chemotherapy. In the first-line (1L) setting, pooled data from the G1T28-05 and G1T28-02 trials, in which trilaciclib or placebo was administered prior to etoposide, carboplatin, and atezolizumab [E/P/A] and E/P, respectively, were used. In the 2/3L setting, analyses were based on data from the G1T28-03 trial where patients received trilaciclib or placebo prior to topotecan. The proportion of patients with single and concurrent multilineage CIM events and incidence rate were estimated per cycle and during the first 4 cycles of chemotherapy. Severe (grade ≥ 3 per CTCAE definition) CIM events of neutropenia (SN), anemia (SA), and thrombocytopenia (ST) were assessed. Concurrent CIM events were defined as having 2 or 3 lineage-specific CIM events overlap for ≥ 1 day. As sensitivity analyses, the occurrence of CIM events in patients with ES-SCLC receiving 1L treatment in the G1T28-05 and G1T28-02 studies was analyzed separately. Results: Compared with placebo, fewer patients receiving trilaciclib had single-lineage CIM events and concurrent events in 2 or 3 lineages during cycles 1–4 of 1L chemotherapy using pooled data from G1T28-05 and G1T28-02 (Table). A similar trend was observed in the 2/3L setting. Generally, SN occurred more frequently in earlier cycles, whereas SA and ST tended to occur later. The sensitivity analysis in each individual 1L trial yielded consistent results with the pooled analysis. Conclusions: Patients with ES-SCLC receiving trilaciclib prior to chemotherapy had fewer single and concurrent multilineage CIM events than patients receiving placebo. Clinical trial information: NCT03041311, NCT02499770, NCT02514447. [Table: see text]
GRECO-2: A randomized, phase 2 study of stereotactic body radiation therapy (SBRT) in combination with rucosopasem (GC4711) in the treatment of locally advanced or borderline resectable nonmetastatic pancreatic cancer.
Authors: Sarah E. Hoffe, Dae Won Kim, James Costello, Mokenge Peter Malafa, Todd Anthony Aguilera, Shaalan Shaalan Beg, Parag Parikh, Joseph M. Herman, Joseph Michael Caster, Maged Ghaly, Elizabeth Charlotte Moser, Kara Terry, Michael Kurman, Jon Holmlund
Journal: Journal of Clinical Oncology (2022)

TPS4184 Background: While treatment of pancreatic cancer has advanced, survival rates remain low. Stereotactic body radiotherapy (SBRT; high dose per fraction radiation) may exhibit improved clinical outcomes in locally advanced pancreatic cancer but carries potential gastrointestinal toxicity risks (Zhong 2017). Rucosopasem (GC4711) is one of a class of investigational selective dismutase mimetics that rapidly and specifically converts superoxide to hydrogen peroxide (Riley 2006). Studies have shown that normal cells tolerate hydrogen peroxide fluxes better than cancer cells (Doskey 2016). As radiation response modifiers, dismutase mimetics have the potential to increase tumor control of SBRT without compromising radiation safety (El-Mahdy 2020, Sishc 2021). In a pilot phase 1/2 trial in patients with pancreatic cancer, avasopasem, a dismutase mimetic related to rucosopasem, nearly doubled median overall survival in patients receiving SBRT vs placebo plus SBRT. Improvements versus placebo were also observed in local tumor control, time to metastases, and progression-free survival. Altogether, these data support the hypothesis that rucosopasem may improve survival and the benefit-risk ratio of SBRT by improving efficacy without increasing gastrointestinal toxicity. Materials/Methods: GRECO-2 is a phase 2, multicenter, randomized, double-blind, placebo-controlled study (NCT04698915) to determine the effect of adding rucosopasem to SBRT on overall survival in patients with borderline resectable or locally advanced, unresectable nonmetastatic pancreatic cancer following initial chemotherapy with a FOLFIRINOX-based regimen or a gemcitabine doublet. Approximately 160 patients will be randomized (approximately 35 sites) to receive rucosopasem 100 mg or placebo via IV infusion over 15 minutes, prior to each SBRT fraction (5 x 10 Gy). Patients judged to be resectable will undergo surgical exploration within 8 weeks after SBRT. The primary endpoint is overall survival. Secondary endpoints include progression-free survival, locoregional control, time to metastasis, surgical resection rate, RO resection rate, best overall response, in-field local response, and safety (acute and late toxicities). Exploratory endpoints include PRO-CTCAE and CA19-9 normalization. This trial is now enrolling. Clinical trial information: NCT04698915.
Upregulation of NKG2D ligands impairs hematopoietic stem cell function in Fanconi anemia
Authors: José A. Casado, Antonio Valeri, Rebeca Sanchez-Domínguez, Paula Vela, Andrea López, Susana Navarro, Omaira Alberquilla, Helmut Hanenberg, Roser Pujol, José-Carlos Segovia, Jordi Minguillón, Jordi Surrallés, Cristina Díaz de Heredia, Julián Sevilla, Paula Rio, Juan A. Bueren
Journal: Journal of Clinical Investigation (2022)

Fanconi anemia (FA) is the most prevalent inherited bone marrow failure (BMF) syndrome. Nevertheless, the pathophysiological mechanisms of BMF in FA have not been fully elucidated. Since FA cells are defective in DNA repair, we hypothesized that FA hematopoietic stem and progenitor cells (HSPCs) might express DNA damage-associated stress molecules such as natural killer group 2 member D ligands (NKG2D-Ls). These ligands could then interact with the activating NKG2D receptor expressed in cytotoxic NK or CD8+ T cells, which may result in progressive HSPC depletion. Our results indeed demonstrated upregulated levels of NKG2D-Ls in cultured FA fibroblasts and T cells, and these levels were further exacerbated by mitomycin C or formaldehyde. Notably, a high proportion of BM CD34+ HSPCs from patients with FA also expressed increased levels of NKG2D-Ls, which correlated inversely with the percentage of CD34+ cells in BM. Remarkably, the reduced clonogenic potential characteristic of FA HSPCs was improved by blocking NKG2D-NKG2D-L interactions. Moreover, the in vivo blockage of these interactions in a BMF FA mouse model ameliorated the anemia in these animals. Our study demonstrates the involvement of NKG2D-NKG2D-L interactions in FA HSPC functionality, suggesting an unexpected role of the immune system in the progressive BMF that is characteristic of FA.
VEGF expression in cetuximab resistance development in patients with squamous cell carcinoma of the tongue and oral mucosa.
Authors: Aza A. Lyanova, Liubov Yu Vladimirova, Elena P. Ulianova, Natalia A. Abramova, Irina L. Popova, Anna E. Storozhakova, Natalia M. Tikhanovskaya, Ludmila A. Ryadinskaya, Maria A. Teplyakova, Sergey N. Kabanov, Elena A. Kalabanova, Irina A. Udalenkova, Marina A. Engibaryan, Irina V. Pustovaya, Maria A. Cherkes, Marina M. Sergeeva
Journal: Journal of Clinical Oncology (2022)

e18072 Background: Clinical course and aggressiveness of a tumor, as well as the subtle mechanisms of its pathogenesis are related to vascularization, which in turn is determined by the ability of transformed cells to synthesize a wide range of biologically active substances. Among modern approaches to cancer treatment, special attention is paid to anti-EGFR agents reducing tumor vascularization. The purpose of this study was to analyze VEGF expression in tumor vessels in patients with squamous cell carcinoma of the tongue and oral mucosa developing cetuximab resistance. Methods: The study included 45 patients with squamous cell carcinoma of the tongue and oral mucosa T3-4N0-1M0. The patients were divided into 3 groups: group 1 – all patients before treatment; group 2 – patients after standard chemotherapy with cisplatin and fluorouracil; group 3 – patients after chemotherapy in combination with targeted therapy with cetuximab. Immunohistochemical study was performed on sections from paraffin blocks of tumors using monoclonal murine anti-VEGF antibodies (clone VG1, Thermo Scientific) diluted 1:150. The Reveal Polyvalent HRP-DAB Detection System was used. The significance of differences was assessed using the Mann Whitney and Wilcoxon tests calculated using the STATISTICA 10.0 program (StatSoftInc., USA). Results: Changes in the density of vessels stained with the VEGF marker were studied in tumor cells of patients in all groups. Patients in group 1 had from 3 to 10 vessels in one field of view; in group 2 – from 2 to 6 vessels in 70% of cases (21) and up to 15 vessels in 30% of cases (9); in group 3 – only solitary vessels. The average numbers of microvessels stained with the VEGF marker per field of view were 6.5±1.52; 4.5±1.71; 1.0±0.28, respectively. Quantification of intratumoral microvascular density showed that the minimum number of microvasculature vessels in the field of view was observed in patients who received chemotherapy and targeted therapy with cetuximab. The value was 5 times lower compared to initial values, and 4 times lower than in patients who received only standard chemotherapy (the Mann Whitney test, p &lt; 0.05). The statistical analysis according to the Wilcoxon test on the effect of targeted therapy (comparison between groups 2 and 3) revealed a statistically significant effect of cetuximab for this marker (p = 0.028). Conclusions: Immunohistochemical analysis of the VEGF neoangiogenesis factor in squamous cell carcinoma of the tongue and oral mucosa confirmed the effectiveness of targeted therapy with cetuximab.
A prognostic model for distant recurrence-free survival in triple-negative breast cancer (TNBC) and the outcomes of initiation of adjuvant chemotherapy in the risk of relapse.
Authors: Zaida Morante, Yomali Ferreyra, Joseph Pinto, Guillermo Valencia, Patricia Elizabeth RiojaViera, Hugo Fuentes, Silvia P. Neciosup, José M. Cotrina, Henry Leonidas Gomez
Journal: Journal of Clinical Oncology (2022)

530 Background: TNBC is a highly complex, heterogenous disease associated with poor outcomes, high incidence of distant metastases, and limited treatment options. With the purpose of identify patients at different risk of distant recurrence, we developed a prognostic model using clinicopathological characteristics that contribute to the risk of recurrence in TNBC patients and also evaluate its influence in the time of beginning of adjuvant therapy. Methods: We retrospectively analyzed 687 TNBC patients who received adjuvant chemotherapy between January 2000 to December 2014 at the Instituto Nacional de Enfermedades Neoplasicas (Lima, Peru). The database was randomly divided into two groups to create a discovery set (n = 344) and a validation set (n = 343). Univariate and multivariate Cox regression analysis was conducted to identify prognostic factors for distant recurrence-free survival (DRFS). We developed a linear risk score based on clinicopathologic characteristics. Under STEPP methodology we classified patients at high, intermediate or low-risk of distant recurrence and the absolute treatment effects of time to initiation of chemotherapy (TTC, ≤ 30 vs &gt; 30 days) through risk subgroups was estimated. Results: The median of follow-up was 9.90 years. In total, 31.0% (n = 213/687) relapses were registered. Variables associated with DRFS in the multivariate analysis were: age, T-staging, and N-staging. A tumor staging of T3-T4 vs. T1/T2 (HR = 2.92, 95%CI: 1.39 - 6.17), followed by the number of positive lymph nodes (N2-N3 vs N0/N1; HR = 2.78, 95%CI: 1.74 - 4.45) and an older age (≥ 60 years vs. ≤ 40/41-59, HR = 2.66, 95%CI: 1.46 - 4.88) were the clinicopathologic characteristics contributing to a higher risk score according to the 3-variable model. Also, 3 risk groups were identified and corroborated in the validation group. In the discovery set, patients with a TTC &gt; 30 days experienced an overall decreased of 17.5% (95%CI: 6.7 - 28.3) in 10-year DFRS vs. those who initiated adjuvant therapy before 30 days. The impact of TTC &gt; 30 days was higher in patients classified as high-risk (Decreased 10-year DFRS: 53.3 ± 28.8 %), similar findings were found in the validation set. Conclusions: A prognostic model based in clinicopathological characteristics (age, pT and pN), was able to classify TNBC patients’ candidates to adjuvant chemotherapy in 3 prognostics groups. We identified a subgroup of patients in which delaying of adjuvant chemotherapy (&gt; 30 days) confers very high-risk of relapse.
Estimating survival benefit of adjuvant chemotherapy in postmenopausal women with pT1-2N0 early-stage breast cancer and Oncotype DX recurrence score &gt; 26: A National Cancer Database (NCDB) analysis.
Authors: Lifen Cao, Christopher W. Towe, Nickolas Stabellini, Amanda L. Amin, Alberto J. Montero
Journal: Journal of Clinical Oncology (2022)

543 Background: Early validation studies using the Oncotype DX recurrence score (RS) in NSABP B20 demonstrated that women with node negative breast cancer and RS &gt;31 had significant survival benefit from the addition of adjuvant chemotherapy to endocrine therapy (CET). Consequently, in the prospective TAILORx trial, node negative women with RS &gt;26 received CET. These studies did not clearly delineate the magnitude of benefit of adjuvant chemotherapy for post-menopausal node negative women. A recently published well-designed adjuvant trial (RxPONDER) demonstrated that adjuvant chemotherapy was not beneficial in post-menopausal pts with ER+/HER2- breast cancer, 1-3 positive nodes, and RS &lt;25. We hypothesized that CET would be associated with a modest but statistically significant overall survival (OS) in women with hormone receptor positive ER+/HER2- node negative breast cancer with RS &gt;26 compared to endocrine therapy (ET) alone, given that CET is more beneficial in women &lt;50 years of age. Methods: The National Cancer Database (NCDB) was queried to analyze women age &gt; 50 with ER+/HER2- pT1-2N0M0 breast cancer with RS &gt;26, to assess real world utilization. We separated women into two groups based on adjuvant treatment: ET alone or CET. Chi-square and logistic regression analysis determined difference between different systemic treatment groups. OS was analyzed using a multivariable Cox model. Results: A total of 16,745 eligible women who underwent surgery and received ET were identified in the NCDB—4,740 (28.3%) received ET alone and 12,005 (71.7%) received CET. We observed that CET use increased over time. Women were more likely to receive CET if their tumors were moderately differentiated (OR = 1.853, p &lt; 0.001), poorly/undifferentiated tumors (OR = 3.875, p &lt; 0.001), or associated with lymph-vascular invasion (OR = 1.206, p = 0.001). After accounting for demographic and oncologic factors, 5-year OS rates in this cohort were significantly superior in women receiving CET compared to ET alone (95.4% vs 92.0%, Hazard Ratio = 0.680, p &lt; 0.001). Conclusions: Utilizing the NCDB to represent real world outcomes, we observed that women &gt; 50 years with pT1-2N0M0 ER+/HER2- breast cancer, and RS &gt; 26 had a significantly superior 5-year OS when receiving adjuvant chemotherapy provides a measurable OS benefit for post-menopausal women in this setting and should be discussed with patients.